Combination Therapies for Cancer Treatment

Abstract

The present invention relates to the combination of certain benzenesulfonamide thiazole compounds with anti-cancer therapies for use in treating cancer in patients identified as overexpressing GRP78. Using a mouse model of colorectal cancer (CT26 allograft model) and several in vitro cancer cell line models, the inventors have shown that combination therapy using the benzenesulfonamide thiazole compound HA15 and anti-cancer therapies, such as immunotherapeutic agents, chemotherapeutic agents, or targeted therapeutic agents, significantly improved survival and potently suppressed tumor growth compared to monotherapy containing either the benzenesulfonamide thiazole compound or the anti-cancer agent alone.

Description

Detailed Description of the Invention

[0001] FIELD OF THE INVENTION The present invention relates to novel cancer treatments, particularly to the combination of anti-cancer treatments with benzenesulfonamide thiazole compounds for use in treating cancer in patients identified as overexpressing GRP78.

[0002] 〔background〕 Cancer encompasses a vast group of diseases characterized by unregulated cell growth and division. Collectively, over 200 known forms of cancer impose a significant societal burden in terms of loss of life, reduced quality of life, medical costs, and lost productivity. Over the past decade, significant improvements have been made in cancer diagnosis, screening, and treatment. Nevertheless, cancer remains a leading cause of death worldwide, killing approximately 10 million people in 2020 (Ferlay et al. Global Cancer Observatory: Cancer Today. Lyon: International Agency for Research on Cancer; 2020).

[0003] Many types of cancer treatments have been developed and are available, including chemotherapy, radiation therapy, and immunotherapy.

[0004] Chemotherapy is often part of the first-line anticancer regimen. Although chemotherapy has shown good results in many cancers, it is also associated with several side effects that can significantly impair a patient's quality of life. Careful management of dosage and regimen is essential to optimize the chances of remission and maintain the patient's health.

[0005] Targeted therapies have been developed to specifically target genes and molecules directly involved in carcinogenesis and tumor growth and have proven to be very useful. These treatments are a form of personalized medicine and, unlike traditional chemotherapy, do not "simply" target rapidly dividing cells. Therefore, targeted therapies are thought to be well tolerated by patients. Unfortunately, the identification of appropriate molecular targets is still in the early stages, and the development of corresponding drugs will take a long time.

[0006] Immunotherapy is now a recognized and well-established treatment option for cancer. Immunotherapy encompasses a group of different treatments, all of which are based on stimulating a patient's immune system to recognize and attack disease. Immunotherapy using immune checkpoint modulators has revolutionized the field of oncology (Robert, C. Nat Commun 11, 3801, 2020). The research that led to the concept of this type of treatment led to the awarding of the Nobel Prize in Medicine to James P. Allison and Tasuku Honjo in 2018. Immune checkpoints refer to numerous inhibitory pathways built into the immune system that are crucial for maintaining autoimmunity, regulating the duration and amplitude of physiological immune responses in peripheral tissues, and minimizing collateral tissue damage resulting from immune responses. When checkpoints and their ligands bind, they send an "off" signal to T cells, inhibiting or strongly suppressing the immune response. It is now clear that tumors use specific immune checkpoint pathways to evade immune responses. Immune checkpoint inhibitors (ICIs) function by preventing checkpoints from binding to their ligands and thus preventing the delivery of "off" signals. These compounds have shown remarkable clinical efficacy and offer great hope for curing some treatment-resistant tumors. Unfortunately, not all tumors respond to immune checkpoint inhibitors. In some cases, the immune system simply cannot detect and attack tumors, even when the inhibitory signals sent by immune checkpoints are turned off. Some tumors are actually non-immunogenic, meaning they cannot be detected by immune cells. Tumor immunogenicity depends on their antigenicity and several other immune regulatory factors produced by either tumor cells or host cells in the tumor microenvironment. Therefore, non-immunogenic tumors do not elicit an immune response, regardless of the presence or absence of inhibitory signals sent to immune cells. Non-immunogenic tumors are generally associated with a poor prognosis and are poorly responsive to most treatment strategies.

[0007] Thus, there is a continuing and urgent need for novel anti-cancer treatments and for the identification of novel molecules that can enhance the effectiveness of known anti-cancer treatments.

[0008] Summary of the Invention The invention is defined by the claims.

[0009] The present inventors have shown that certain benzenesulfonamide thiazole compounds have the ability to significantly enhance the effects of anti-cancer treatments, including chemotherapy, targeted therapy, and immunotherapy. The specific benzenesulfonamide thiazole compounds used in accordance with the present invention are disclosed in the international application published under the number WO2014 / 07248. They have anti-cancer activity and target GRP78. Surprisingly, the effects obtained when these compounds are used in combination with anti-cancer treatments are significantly higher than the effects obtained when each treatment is used alone.

[0010] The inventors further demonstrated that such combination therapy resulted in significant tumor growth inhibition, tumor regression, and better overall survival in patients overexpressing either circulating or intratumoral GRP78.

[0011] Overexpression of GRP78 has been linked to ovarian cancer (Samanta et al. Scientific reports 10.1 (2020): 1-12), melanoma (Shimizu et al. Pathology & Oncology Research 23.1 (2017): 111-116), lung cancer (Xia et al. Journal of Translational Medicine 19.1 (2021): 1-14), gastric cancer (Zhang et al. Clinical & experimental metastasis 23.7 (2006): 401-410), breast cancer (Oncology letters 10.4 (2015): 2149-2155), esophageal cancer (Zhao et al. Digestive diseases and sciences 60.9 (2015): 2690-2699), and pancreatic cancer (Tong et al. Pancreatology 21.7 (2021): It has been shown that GRP78 is associated with poor prognosis in many cancers, such as rectal cancer (Thornton et al. International journal of cancer 133.6 (2013): 1378-1385), or colorectal cancer (Thornton et al. International journal of cancer 133.6 (2013): 1408-1418). The inventors have shown that the combination according to the invention makes it possible to significantly reduce intratumoral and circulating levels of GRP78 in patients, compared to monotherapy comprising either a benzenesulfonamide thiazole compound or said "traditional" anticancer treatment.

[0012] Therefore, combination therapy according to the present invention may be particularly beneficial for patients who exhibit high levels of GRP78 and are identified as having a poor prognosis.

[0013] Thus, the present invention provides a combination of an anti-cancer treatment with a benzenesulfonamide thiazole compound of formula (I): [ka] During the ceremony, Q1 to Q5 are the same or different and represent CR6; R1 is a C6-C fused ring 10 aryl, wherein 2 to 5 carbon atoms may be replaced by heteroatoms selected from O, S, N, and NR6, including R6, halo, CN, NO2, CF3, OCF3, COOR6, OCOR6, SO2NR6R7, CONR6R7, NR6R7, NR6COR7, (CH2) p- NR6R7, (CH2) p- OR6 and (CH2) P is ultimately substituted with 5 to 11 substituents selected from SR6; R2 is SO2R1 or R6, R3 and R4 are the same or different and are selected from COR8 and R6; R5 represents R6, aryl, OR6, SR6, halo, CN, NO2, CF3, OCF3, COOR6, SO2NR6R7, CONR6R7, NR6R7, and NHCOR6; R6 and R7 are the same or different and represent H or alkyl; R8 is selected from H, alkyl, cycloalkyl, aryl, alkylaryl, where the aryl is optionally substituted with 1 to 4 identical or different R5 substituents; Or R8 is -(CH2) q -NR6R7, p represents an integer of 0 to 6; q represents an integer of 0 to 6, wherein the thiazolyl group is linked to the six-membered group at the meta or para position relative to the sulfonamide group, and the thiazolyl group is linked to the six-membered group at the alpha or beta position relative to the S atom; The combination is for use in treating cancer in patients identified as overexpressing GRP78.

[0014] Detailed Description Using several cancer mouse models (e.g., colorectal CT26 allograft model) and in vitro cancer cell line models (e.g., melanoma, myeloma, gastric cancer, pancreatic cancer, and colorectal cancer cell lines), the inventors have shown that combination therapy using benzenesulfonamide thiazole compounds and "conventional" anticancer treatments significantly improved survival and potently suppressed tumor growth compared to monotherapy containing either benzenesulfonamide thiazole compounds or the "conventional" anticancer treatments. The inventors also showed that mice receiving the combination treatments had significantly reduced levels of circulating and intratumoral GRP78 compared to vehicle and "conventional" anticancer treatments.

[0015] The inventors have clearly demonstrated a strong synergistic effect between compounds such as immune checkpoint inhibitors and the benzenesulfonamide thiazole compounds disclosed herein. Without wishing to be bound by theory, the inventors propose that the benzenesulfonamide thiazole compounds described herein render tumors immunogenic, i.e., detectable by the immune system, thereby enabling enhanced anti-cancer effects of combined anti-cancer treatments. The inventors have also shown that the specific combination of benzenesulfonamide thiazole compounds and anti-cancer treatments is particularly advantageous in patients overexpressing GRP78.

[0016] Thus, the present invention provides a highly promising therapeutic approach for the treatment of cancer.

[0017] Thus, in a first aspect, the present invention provides a combination of an anti-cancer treatment and a benzenesulfonamide thiazole of formula (I): [ka] (In the formula, Q1 to Q5 are the same or different and represent CR6; R1 is a C6-C fused ring 10aryl, wherein 2 to 5 carbon atoms may be replaced by heteroatoms selected from O, S, N, and NR6, including R6, halo, CN, NO2, CF3, OCF3, COOR6, OCOR6, SO2NR6R7, CONR6R7, NR6R7, NR6COR7, (CH2) p- NR6R7, (CH2) p- OR6 and (CH2) P is ultimately substituted with 5 to 11 substituents selected from SR6; R2 is SO2R1 or R6, R3 and R4 are the same or different and are selected from COR8 and R6; R5 represents R6, aryl, OR6, SR6, halo, CN, NO2, CF3, OCF3, COOR6, SO2NR6R7, CONR6R7, NR6R7, and NHCOR6; R6 and R7 are the same or different and represent H or alkyl; R8 is selected from H, alkyl, cycloalkyl, aryl, alkylaryl, where the aryl is optionally substituted with 1 to 4 identical or different R5 substituents; Or R8 is -(CH2) q -NR6R7, p represents an integer of 0 to 6; q represents an integer of 0 to 6, wherein the thiazolyl group is linked to the six-membered group at the meta or para position relative to the sulfonamide group, and the thiazolyl group is linked to the six-membered group at the alpha or beta position relative to the S atom), or, where appropriate, in combination with a pharmaceutically acceptable salt and / or isomer, tautomer, solvate or isotopic variant thereof, The combination is for use in treating cancer in patients identified as having overexpressed GRP78.

[0018] "Combinations" for use in accordance with the present invention include: - an anti-cancer treatment / agent for use in the treatment of cancer, said anti-cancer agent being used in combination with a benzenesulfonamide thiazole of formula (I) as defined above; and - a benzenesulfonamidothiazole of formula (I) as defined above for use in the treatment of cancer, said benzenesulfonamidothiazole being used in combination with an anti-cancer agent; It encompasses both.

[0019] "Combinations" for use in accordance with the present invention include: - anticancer drugs; and a compound of formula (I) as defined above, Also encompassed is a kit of parts for use in treating cancer in a patient identified as overexpressing GRP78, comprising:

[0020] As used herein, the term "kit of parts" refers to a combination formulation in which the active ingredients are physically separated for use in combination therapy by simultaneous or sequential administration to a patient. Thus, according to the present invention, an anticancer drug and a compound of formula (I) are administered to a patient in separate forms simultaneously, separately, or sequentially in any order for the treatment of cancer.

[0021] According to a further embodiment, the present invention also relates to a kit of parts per se, namely comprising: - anticancer drugs; and a compound of formula (I) as defined above, Parts kit including:

[0022] [Anti-cancer treatment / anti-cancer drug] According to the present invention, the anti-cancer treatment is any anti-cancer agent selected from chemotherapy, targeted therapy, immunotherapy and combinations thereof.

[0023] "Chemotherapy," "chemotherapeutics," and "chemotherapeutic agents" refer to chemicals effective in inhibiting tumor growth. Examples of chemotherapeutic agents include: alkylating agents such as thiotepa and cyclophosphamide; alkylsulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, metturdopa, and urdopa; ethylenimines and methylamines such as altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphaoralnide, and trimethylolmelamine; acetogenins (especially bullatacin and bullatacinone); camptothecins (including irinotecan and topotecan); bryostatin; kallistatin; CC-1065 (including its adozelesin, carzelesin, and bizelesin synthetic analogs); cryptophycins (especially cryptophycin 1 and cryptophycin 8); dolastatins; duocarmycins (including synthetic analogs KW-2189 and CBI-TMI); eleutherobin; pancratistatin; sarcodictine; spongistatins; nitrogen mustards such as chlorambucil, chlornaphazine, colofosfamide, estralnustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, nobembitine, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine; antibiotics such as enediyne antibiotics (e.g., calicheamicins, particularly calicheamicin 11 and calicheamicin 211, e.g., Agnew Chem Intl. Ed. Engl. 33:183-186 (1994)); dynemicins such as dynemicin A; esperamicin;and neocarzinostatin chromophore and related chromoproteins, enediin antiobiotic chromophore, aclacinomycin, actinomycin, autramycin, azaserine, bleomycin, cactinomycin, carabicin, caninomycin, carzinophilin, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin (morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin, and deoxydoxol). (including bicin), epirubicin, esorubicin, idanrubicin, marcelomycin, mitomycin, mycophenolic acid, nogalarnicin, olivomycin, peplomycin, potfilomycin, puromycin, keramicin, rodorubicin, streptomugrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, and trimetrexate; fludarabine, 6-mercaptopropionate Purine analogs such as thiamiprine, thiamiprine, and thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmophor, cytarabine, dideoxyuridine, doxifluridine, enocitabine, and floxuridine; androgens such as calsterone, dromostanolone propionate, epithiostanol, mepitiostane, and testolactone; antiadrenergics such as aminoglutethimide, mitotane, and trilostane; folic acid supplements such as furoic acid; aceglatone; aldophosphamide glycosides; aminolevulinic acid; ansacrine; Bestra Bucil; Bisantrene; Edatraxate; Defofamine; Demecolcine; Diaziquion; Elfornicin; Elliptinium acetate; Epothilone; Etoglucide; Gallium nitrate; Hydroxyurea; Lentinan; Lonidamine; Maytansinoids such as maytansine and ansamitocin; Mitoguazone; Mitoxantrone; Mopidamol; Nitracrine; Pentostatin; Fenamet; Pirarubicin; Podophyllic acid; 2-ethylhydrazide; Procarbazine; PSK (registered trademark); Razoxane; Rhizoxin; Sizofiran; Spirogenanium; Tenuazonic acid;triazicon; 2,2',2''-trichlorotriethylarnine; trichothecenes (especially T-2 toxin, veraculin A, roridin A, and anguidine); urethane; vindesine; dacarbazine; mannomustine; mitobromtol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoids, such as paclitaxel (TAXOL®, Bristol-Myers Squibb Oncology, Princeton, N.M.), and docetaxel (TAXOTERE®, Rhone-Poulenc Rorer, Antony, France); chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin, carboplatin, oxaloplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin; aminopterin; xeloda; ibandronate; CPT-1; topoisomerase inhibitor RFS2000; difluoromethylornithine (DMFO); retinoic acid; capecitabine; and pharmaceutically acceptable salts, acids, or derivatives of any of the above. Also included in this definition are antihormonal agents that act to modulate or inhibit the action of hormones on tumors, e.g., antiestrogens such as tamoxifen, raloxifene, aromatase-inhibiting 4(5)-imidazole, 4-hydroxytamoxifen, trioxifene, ketoxifene, LY117018, onapristone, and toremifene (Farestone); antiandrogens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; and pharmaceutically acceptable salts, acids, or derivatives of any of the above.

[0024] According to a preferred embodiment, chemotherapeutic agents for use in the context of the present invention are selected from toxoids such as doxorubicin, paclitaxel and docetaxel, antimetabolites such as gemcitabine, methotrexate and 5-fluorouracil (5-FU), platinum analogues such as cisplatin and oxaloplatin, and camptothecins such as irinotecan and topotecan.

[0025] "Targeted therapy" refers to a drug that inhibits the growth of cancer cells by inhibiting specific target molecules necessary for carcinogenesis and tumor growth. Most targeted therapies are either small molecule drugs or monoclonal antibodies. It is noteworthy that some targeted therapies qualify as immunotherapeutic agents and / or chemotherapeutic agents. Examples of targeted therapies include BRAF inhibitors such as bortezomib, vemurafenib, and dabrafenib; Janus kinase inhibitors such as cobimetinib, imatinib, gefitinib, erlotinib, sorafenib, sunitinib, dasatinib, lapatinib, nilotinib, tamoxifen, and tofacitinib; ALK inhibitors such as crizotinib; Bcl-2 inhibitors such as venetoclax, obatoclax, navitoclax, and gossypol; PARP inhibitors such as olaparib, rucaparib, niraparib, and talazoparib; and peritoneal anti-cancer drugs. These include PI3K inhibitors such as phosine, MEK inhibitors such as apatinib, zoptarelin, doxorubicin, and trametinib, CDK inhibitors, Hsp90 inhibitors, hedgehog pathway inhibitors such as vismodegib and sonidegib, salinomycin VAL-083, vintafolide, temsirolimus, everolimus, vemurafenib, trametinib, dabrafenib, pembrolizumab, rituximab, alemtuzumab, cetuximab, panitumumab, bevacizumab, and ipilimumab.

[0026] According to certain embodiments, the targeted therapy for use according to the present invention is selected from bortezomib, vemurafenib and cobimetinib.

[0027] "Immunotherapy," "immunotherapeutics," or "immunotherapeutic agent" refers to compounds, compositions, or treatments that indirectly or directly enhance, stimulate, or increase the body's immune response to cancer cells and / or reduce the side effects of other anti-cancer therapies. That is, immunotherapy is a therapy that directly or indirectly stimulates or enhances the immune system's response to cancer cells and / or reduces side effects that may be caused by other anti-cancer drugs. Immunotherapy is also referred to in the art as immunological therapy, biological therapy, biological response modifier therapy, and biotherapy. Examples of common immunotherapeutic agents known in the art include, but are not limited to, cytokines, cancer vaccines, monoclonal antibodies, and non-cytokine adjuvants. Alternatively, immunotherapy may consist of administering to a patient an amount of immune cells (T cells, NK cells, dendritic cells, B cells, etc.).

[0028] Immunotherapeutic agents may be nonspecific, i.e., they generally enhance the immune system so that the human body is more effective in fighting cancer cell growth and / or metastasis, or they may be specific, i.e., they target the cancer cells themselves. Immunotherapeutic regimens may combine the use of nonspecific and specific immunotherapeutic agents.

[0029] Nonspecific immunotherapeutic agents are substances that stimulate or indirectly improve the immune system. Nonspecific immunotherapeutic agents are used not only alone as the main treatment for cancer treatment, but also in addition to the main treatment, in which case they function as adjuvants that enhance the effectiveness of other treatments (e.g., cancer vaccines). Nonspecific immunotherapeutic agents may act on key immune system cells and induce secondary responses such as increased production of cytokines and immunoglobulins. Alternatively, the agent itself may contain cytokines. Nonspecific immunotherapeutic agents are generally classified as cytokine or non-cytokine adjuvants.

[0030] A number of cytokines have been applied in the treatment of cancer, either as general non-specific immunotherapy designed to boost the immune system or as adjuvants in combination with other therapies. Suitable cytokines include, but are not limited to, interferons, interleukins, and colony-stimulating factors.

[0031] Interferons (IFNs) include the common types IFN-alpha (IFN-a), IFN-beta (IFN-beta), and IFN-gamma (IFN-y). IFNs may act directly on cancer cells, for example, by slowing their growth, promoting their progression toward more normal-behaving cells, and / or increasing their production of antigens, making them easier for the immune system to recognize and destroy. IFNs may also act indirectly on cancer cells, for example, by reducing angiogenesis, activating the immune system, and / or stimulating natural killer (NK) cells, T cells, and macrophages. Recombinant IFN-alpha is commercially available as Roferon (Roche Pharmaceuticals) and Intron A (Schering Corporation). The use of IFN-alpha alone, in combination with other immunotherapies, or in combination with chemotherapy has shown efficacy in the treatment of various cancers, including melanoma (including metastatic melanoma), renal cancer (including metastatic renal cancer), breast cancer, prostate cancer, and cervical cancer (including metastatic cervical cancer).

[0032] Interleukins include IL-2, IL-4, IL-11, and IL-12. Examples of commercially available recombinant interleukins include Proleukin® (IL-2; Chiron Corporation) and Neumega® (IL-12; Wyeth Pharmaceuticals). Interleukins, alone or in combination with other immunotherapies or chemotherapy, have shown efficacy in the treatment of a variety of cancers, including renal cancer (including metastatic renal cancer), melanoma (including metastatic melanoma), ovarian cancer (including recurrent ovarian cancer), cervical cancer (including metastatic cervical cancer), breast cancer, colorectal cancer, lung cancer, brain cancer, and prostate cancer.

[0033] Colony-stimulating factors (CSFs) include granulocyte colony-stimulating factor (G-CSF or filgrastim), granulocyte-macrophage colony-stimulating factor (GM-CSF or sargramostim), and erythropoietin (epoetin alfa, darbepoietin). Various recombinant colony-stimulating factors are commercially available, such as Neupogen® (G-CSF; Amgen), Neulasta (perfilgrastim; Amgen), Leukin® (GM-CSF; Berlex), Procrit® (erythropoietin; Ortho Biotech), Epogen® (erythropoietin; Amgen), and Ernesp® (erythropoietin). Colony-stimulating factors have shown efficacy in the treatment of cancers, including melanoma, colorectal cancer (including metastatic colorectal cancer), and lung cancer.

[0034] Non-cytokine adjuvants suitable for use in the combinations of the present invention include, but are not limited to, levamisole, alum hydroxide (alum), bacillus Calmette-Guerin (ACG), incomplete Freund's adjuvant (IFA), QS-21, DETOX, keyhole limpet hemocyanin (KLH), and dinitrophenyl phosphate (DNP). Non-cytokine adjuvants have demonstrated efficacy in combination with other immunotherapies and / or chemotherapy against a variety of cancers, including, for example, colon and colorectal cancer (levamisole); melanoma (BCG and QS-21); and renal and bladder cancer (BCG).

[0035] In addition to having a specific or non-specific target, immunotherapeutics may be active, i.e., stimulate the body's own immune response, or passive, i.e., involve immune system components generated outside the body.

[0036] Active specific immunotherapy typically involves the use of cancer vaccines. Cancer vaccines have been developed that contain whole cancer cells, parts of cancer cells, or one or more antigens derived from cancer cells. Cancer vaccines, alone or in combination with one or more immunotherapeutic or chemotherapeutic agents, have been studied in the treatment of several types of cancer, including melanoma, renal cancer, ovarian cancer, breast cancer, colorectal cancer, and lung cancer.

[0037] Immunotherapy may consist of adaptive immunotherapy, as described by Nicholas P. Restifo, Mark E. Dudley, and Steven A. Rosenberg in "Adoptive immunotherapy for cancer: harnessing the T cell response" (Nature Reviews Immunology, Volume 12, April 2012). In adoptive immunotherapy, a patient's circulating or tumor-infiltrating lymphocytes are isolated in vitro, activated with lymphokines such as IL-2, or transduced with tumor necrosis genes, and then re-administered (Rosenberg et al., 1988; 1989). The activated lymphocytes are most preferably the patient's own cells, isolated from blood or tumor samples and activated (or "expanded") in vitro. Several cases have been reported in which this form of immunotherapy resulted in regression of melanoma and renal carcinoma.

[0038] Passive specific immunotherapy typically involves the use of one or more monoclonal antibodies specific for a particular antigen found on the surface of cancer cells or specific for a particular cell growth factor. Monoclonal antibodies can be used in cancer treatment in many ways, such as to enhance a patient's immune response to a particular type of cancer, to inhibit the growth of cancer cells by targeting specific cell growth factors such as those involved in angiogenesis, or by enhancing the delivery of other anti-cancer drugs to cancer cells when linked or conjugated to drugs such as chemotherapeutic agents, radioactive particles, or toxins.

[0039] Monoclonal antibodies currently used as cancer immunotherapeutics suitable for inclusion in the combinations of the present invention include, but are not limited to, rituximab (Rituxan®), trastuzumab (Herceptin®), ibritumomab tiuxetan (Zevalin®), tositumomab (Vexar®), cetuximab (C-225, Erbitux®), bevacizumab (Avastin®), gemtuzumab ozogamicin (Mylotarg®), alemtuzumab (Campus®), and BL22. Monoclonal antibodies are used to treat a wide range of cancers, including breast cancer (including advanced metastatic breast cancer), colorectal cancer (including advanced and / or metastatic colorectal cancer), ovarian cancer, lung cancer, prostate cancer, cervical cancer, melanoma, and brain cancer. Other examples include immune checkpoint inhibitors.

[0040] The term "immune checkpoint protein" is widely known in the art and refers to a molecule expressed by T cells that either upregulates (stimulatory checkpoint molecules) or downregulates (inhibitory checkpoint molecules). Immune checkpoints constitute immune checkpoint pathways, such as the CTLA-4 and PD-1-dependent pathways (see, e.g., Pardoll, 2012. Nature Rev Cancer 12:252-264; Mellman et al., 2011. Nature 480:480-489). Examples of inhibitory checkpoint molecules include A2AR, B7-H3, B7-H4, BTLA, CTLA-4, CD277, IDO1, KIR, PD-1, LAG-3, TIM-3 TIGIT, and VISTA.

[0041] A2AR ("Adenosine A2A receptor") is considered an important checkpoint in cancer therapy: the presence of adenosine in the immune microenvironment leads to activation of A2a receptors, inducing a negative immune feedback loop, and the tumor microenvironment has a relatively high concentration of adenosine. B7-H3, also known as CD276, was originally understood as a costimulatory molecule but is now considered a coinhibitory molecule. B7-H4, also known as VTCN1, is expressed by tumor cells and tumor-associated macrophages and is involved in tumor escape. BTLA ("B and T Lymphocyte Attenuator"), also known as CD272, has HVEM (Herpesvirus Entry Mediator) as a ligand. Surface expression of BTLA is associated with human CD8 + It is gradually downregulated during the differentiation of T cells from naive to effector cell phenotypes. Tumor-specific human CD8 + T cells express high levels of BTLA. Expression of CTLA-4 ("Cytotoxic T-Lymphocyte-Associated protein 4"), also known as CD152, on Treg cells controls T cell proliferation. IDO1 ("Indoleamine 2,3-dioxygenase 1") is a tryptophan catabolic enzyme and an immunosuppression-related enzyme. IDO1 is known to suppress T cells and NK cells, generate and activate Tregs and myeloid-derived suppressor cells, and promote tumor angiogenesis. KIR ("Killer-cell Immunoglobulin-like Receptor") is a receptor for MHC class I molecules on natural killer cells. LAG3 ("Lymphocyte Activation Gene-3") acts on Tregs and activates CD8 +It suppresses immune responses through a direct inhibitory effect on T cells. The PD-1 ("Programmed Death 1") receptor has two ligands, PD-L1 and PD-L2. This checkpoint is the target of pembrolizumab, marketed by Merck. Targeting PD-1 can restore immune function in the tumor microenvironment. TIM-3 ("T-cell Immunoglobulin domain and Mucin domain 3") is a receptor that binds to activated human CD4 + It is expressed on T cells and regulates Th1 and Th17 cytokines. TIM-3 acts as a negative regulator of Th1 / Tc1 function by inducing cell death through interaction with its ligand, galectin-9. VISTA ("V-domain Ig suppressor of T cell activation") is primarily expressed on hematopoietic cells. VISTA is consistently expressed on leukocytes within tumors, making VISTA blockade effective against a wide range of solid tumors. TIGIT ("T cell immunoreceptor with Ig and ITIM domains") is an immunoreceptor present on a proportion of T cells and natural killer (NK) cells. TIGIT inhibits T cell activation in vivo.

[0042] "Immune checkpoint inhibitor" or "checkpoint blockade cancer immunotherapeutic" has its general meaning in the art and refers to any compound that inhibits the function of immune inhibitory checkpoint proteins. Inhibition includes reduction of function and complete blockade. Immune checkpoint inhibitors include peptides, antibodies, nucleic acid molecules, and small molecules. Preferred immune checkpoint inhibitors are antibodies that specifically recognize immune checkpoint proteins. Immune checkpoint inhibitors as used in the context of the present invention inhibit CD8 expression in patients. + It is administered to enhance the proliferation, migration, persistent survival and / or cytotoxic activity of T cells. + T cells are a subset of T cells that express CD8 on their surface. +T cells are MHC class I restricted and function as cytotoxic T cells. CD8 + T cells are also called cytotoxic T lymphocytes (CTLs), T killer cells, cytolytic T cells, CD8+ T cells, or killer T cells. The CD8 antigen is a member of the immunoglobulin supergene family and is the binding recognition element in major histocompatibility complex class I-restricted interactions. CD8 + The ability of an immune checkpoint inhibitor to enhance the killing activity of T cells can be determined by any assay known in the art. Typically, the assay is + T cells to target cells (e.g., CD8 + For example, immune checkpoint inhibitors of the present invention may be used in in vitro assays in which the immune checkpoint inhibitors are contacted with CD8 T cells (target cells that are recognized and / or lysed by CD8 T cells). + They may be selected for their ability to increase specific lysis by T cells by more than about 20%, preferably at least about 30%, at least about 40%, at least about 50%, or more. Examples of classical cytotoxicity assay protocols are conventional.

[0043] Typically, immune checkpoint inhibitors are agents that inhibit immunoinhibitory receptors expressed by activated T lymphocytes, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA4) and programmed cell death 1 (PDCD1, also known as PD-1), or by NK cells, such as various members of the killer cell immunoglobulin-like receptor (KIR) family, or the primary ligands for these receptors, such as the PD-1 ligand CD274 (best known as PD-L1 or B7-H1).

[0044] Typically, checkpoint blockade cancer immunotherapeutics are antibodies.

[0045] In some embodiments, the checkpoint blockade cancer immunotherapeutic is an antibody selected from the group consisting of an anti-PD1 antibody, an anti-PDL1 antibody, an anti-PDL2 antibody, an anti-CTLA4 antibody, an anti-TIM-3 antibody, an anti-LAG3 antibody, an anti-IDO1 antibody, an anti-TIGIT antibody, an anti-B7H3 antibody, an anti-B7H4 antibody, an anti-BTLA antibody, and an anti-B7H6 antibody.

[0046] Examples of anti-PD-1 antibodies, anti-PD-L1 antibodies, and anti-PD-L2 antibodies are described in U.S. Patent Nos. 7,488,802; 7,943,743; 8,008,449; 8,168,757; and 8,217,149, and PCT published patent applications WO03042402, WO2008156712, WO2010089411, WO2010036959, WO2011066342, WO2011159877, WO2011159877, WO2011082400, and WO2011161699. In some embodiments, the PD-1 blocker comprises an anti-PD-L1 antibody (e.g., atezolizumab, avelumab, or durvalumab). In other embodiments, the PD-1 blocker comprises an anti-PD-L2 antibody. In certain other embodiments, PD-1 blockers include anti-PD-1 antibodies and similar binding proteins, such as nivolumab (MDX1106, BMS936558, ONO4538), a fully human IgG4 antibody that binds to and inhibits activation of PD-1 by its ligands PD-L1 and PD-L2; lambrolizumab (MK-3475 or SCH900475), a humanized monoclonal IgG4 antibody against PD-1; CT-011, a humanized antibody that binds to PD-1; AMP-224, a fusion protein of B7-DC; the Fc portion of an antibody; or BMS-936559 (MDX-1105-01) for PD-L1 (B7-H1) blockade.

[0047] Examples of anti-CTLA-4 antibodies are described in U.S. Patent Nos. 5,811,097; 5,811,097; 5,855,887; 6,051,227; 6,207,157; ​​6,682,736; 6,984,720; and 7,605,238. One anti-CTLA-4 antibody is tremelimumab (ticilimumab, CP-675,206). In some embodiments, the anti-CTLA-4 antibody is ipilimumab (10D1, also known as MDX-D010), a fully human monoclonal IgG antibody that binds to CTLA-4.

[0048] Other immune checkpoint inhibitors include lymphocyte activation gene-3 (LAG-3) inhibitors, such as IMP321, a soluble Ig fusion protein (Brignone et al., 2007, J. Immunol. 179:4202-4211).

[0049] Other immune checkpoint inhibitors include B7 inhibitors, such as B7-H3 and B7-H4 inhibitors, in particular the anti-B7-H3 antibody MGA271 (Loo et al., 2012, Clin. Cancer Res. July 15 (18) 3834).

[0050] Also included are TIM3 ("T-cell immunoglobulin domain and mucin domain 3") inhibitors (Fourcade et al., 2010, J. Exp. Med. 207:2175-86 and Sakuishi et al., 2010, J. Exp. Med. 207:2187-94). The natural ligand of TIM-3 is galectin-9 (Gal9). Thus, the term "TIM-3 inhibitor" as used herein refers to a compound, substance, or composition capable of inhibiting the function of TIM-3. For example, the inhibitor may inhibit the expression or activity of TIM-3, modulate or block the TIM-3 signaling pathway, and / or block the binding of TIM-3 to galectin-9. Antibodies with specificity for TIM-3 are known in the art, typically those described in WO2011155607, WO2013006490, and WO2010117057.

[0051] In some embodiments, the immune checkpoint inhibitor is an indoleamine 2,3-dioxygenase (IDO) inhibitor, preferably an IDO1 inhibitor. Examples of IDO inhibitors are described in WO2014150677. Examples of IDO inhibitors include, but are not limited to, 1-methyl-tryptophan (IMT), β-(3-benzofuranyl)-alanine, β-(3-benzo(b)thienyl)-alanine, 6-nitro-tryptophan, 6-fluoro-tryptophan, 4-methyl-tryptophan, 5-methyltryptophan, 6-methyl-tryptophan, 5-methoxy-tryptophan, 5-hydroxy-tryptophan, indole-3-carbinol, 3,3'-diindolylmethane, epigallocatechin gallate, 5-Br-4-Cl-indoxyl 1,3-diacetate, 9-vinylcarbazole, acemetacin, 5-bromo-tryptophan, 5-bromoindoxyl diacetate, 3-amino-naphthoic acid, pyrrolidine dithiocarbamate, 4-phenylimidazole brassinin derivatives, thiohydantoin derivatives, β-carboline derivatives, or brassilexin derivatives. Preferably, the IDO inhibitor is selected from 1-methyl-tryptophan, β-(3-benzofuranyl)-alanine, 6-nitro-L-tryptophan, 3-amino-naphthoic acid, and β-[3-benzo(b)thienyl]-alanine, or a derivative or prodrug thereof.

[0052] In some embodiments, the immune checkpoint inhibitor is an anti-TIGIT (T cell immunoglobulin and ITIM domain) antibody.

[0053] According to a particular embodiment, the anti-cancer treatment according to the invention is an immune checkpoint inhibitor, preferably selected from anti-PD-1 antibodies and anti-PD-L1 antibodies.

[0054] In a preferred embodiment, the checkpoint blockade cancer immunotherapeutic is a PD-1 inhibitor antibody, such as nivolumab or pembrolizumab.

[0055] [Compound of formula (I)] The benzenesulfonamide thiazole compounds of formula (I) used in the context of the present invention have been extensively disclosed and studied in the international patent application published under reference number WO2014 / 072486, the contents of which are incorporated herein by reference in their entirety.

[0056] According to a preferred embodiment, the compounds of formula (I) used in the context of the present invention also correspond to formula (II): [ka] In the formula, Q1 to Q5, R2, R3, R4, and R5 are as defined above, and R9 is R6, halo, CN, NO2, CF3, OCF3, COOR6, OCOR6, SO2NR6R7, CONR6R7, NR6R7, NR6COR7, (CH2) p- NR6R7, (CH2) p- OR6 and (CH2) P Represents SR6.

[0057] wherein R6, R7 and p are as defined above, n represents 1, 2, 3 or 4, and the naphthyl group is attached to the sulfur atom at the 1-, 2- or 3-position relative to the quaternary carbon.

[0058] In the above general formula (I) or (II): R2 preferably represents H, R3 preferably represents H, R4 is preferably CO-alkyl, R6 is preferably H or alkyl, R9 is preferably NR6R7, where R6 and R7 both preferably represent CH3; The thiazolyl group is preferably in the meta position relative to the sulfonamide group and is preferably linked to the six-membered aromatic ring in the beta position relative to the sulfur atom.

[0059] In the above general formulas (I) and (II), alkyl denotes a straight-chain or branched group containing 1, 2, 3, 4 or 5 carbon atoms. This also applies when they have a substituent or when they occur as a substituent of other radicals, for example, in O-alkyl radicals, S-alkyl radicals, etc. Examples of suitable alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, etc.

[0060] Cycloalkyl contains 3 to 7 carbon atoms and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0061] Aryl refers to an aromatic carbocyclic ring containing 6 to 10 carbon atoms.

[0062] Finally, halo denotes a halogen atom selected from the group consisting of fluoro, chloro, bromo and iodo, in particular fluoro or chloro.

[0063] Preferably, in formulae (I) and (II), the free bond on the phenyl group means that the phenyl can be substituted at the meta or para position.

[0064] Preferred compounds according to the invention are: N-(4-(3-(5-(dimethylamino)naphthalene-l-sulfonamido)phenyl)thiazol-2-yl)acetamide 5-(dimethylamino)-N-(3-(2-(methylamino)thiazol-4-yl)phenyl)naphthalene-l-sulfonamide N-(4-(3-(5-(dimethylamino)naphthalene-l-sulfonamido)phenyl)thiazol-2-yl)-4-methylbenzamide N-(3-(2-aminothiazol-4-yl)phenyl)-5-(dimethylamino)naphthalene-l-sulfonamide N-(4-(3-(5-(dimethylamino)naphthalene-l-sulfonamido)phenyl)thiazol-2-yl)benzamide N-(4-(3-(5-(dimethylamino)naphthalene-l-sulfonamido)phenyl)thiazol-2-yl)pivalamide 2-Fluoro-N-(3-(2-(methylamino)thiazol-4-yl)phenyl)benzenesulfonamide N-(4-(4-(naphthalene-2-sulfonamido)phenyl)thiazol-2-yl)acetamide N-(4-(4-(5-(dimethylamino)naphthalene-l-sulfonamido)phenyl)thiazol-2-yl)acetamide N-(4-(4-(2-fluorophenylsulfonamido)phenyl)thiazol-2-yl)acetamide N-(4-(4-(2,4-difluorophenylsulfonamido)phenyl)thiazol-2-yl)acetamide N-(4-(4-(3-(trifluoromethyl)phenylsulfonamido)phenyl)thiazol-2-yl)acetamide N-(4-(3-(3-(trifluoromethyl)phenylsulfonamido)phenyl)thiazol-2-yl)acetamide N-(4-(4-(4-(trifluoromethyl)phenylsulfonamido)phenyl)thiazol-2-yl)acetamide N-(4-(3-(4-methylphenylsulfonamido)phenyl)thiazol-2-yl)acetamide N-(4-(3-(2-nitrophenylsulfonamido)phenyl)thiazol-2-yl)acetamide N-(4-(3-(3-nitrophenylsulfonamido)phenyl)thiazol-2-yl)acetamide N-(4-(3-(phenylsulfonamido)phenyl)thiazol-2-yl)acetamide N-(4-(3-(methylsulfonamido)phenyl)thiazol-2-yl)acetamide N-(4-(4-(4-methylphenylsulfonamido)phenyl)thiazol-2-yl)acetamide, and N-(4-(3-(5-(dimethylamino)naphthalene-l-sulfonamido)phenyl)thiazol-2-yl)-6-amino-hexanamide.

[0065] According to a more preferred embodiment, the benzenesulfonamide thiazole compound of formula I used in the context of the present invention corresponds to formula (III): [ka]

[0066] The compound of formula (III) is also referred to in the context of the present invention as compound "HA15".

[0067] Methods for the synthesis of benzenesulfonamide thiazole compounds useful according to the present invention are disclosed in the above-mentioned application WO2014 / 072486.

[0068] The benzenesulfonamide thiazole compounds of formula (I), (II) and (III) may be in the form of pharmaceutically acceptable salts, including acid addition and base salts thereof.

[0069] Suitable acid addition salts are formed from acids which form non-toxic salts, such as acetate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, glucopate, gluconate, glucuronate, hexafluorophosphate, bibenzoate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, saccharate, stearate, succinate, tartrate, tosylate, trifluoroacetate, and xinafoate.

[0070] Suitable base salts are formed from bases that form non-toxic salts. Examples include aluminum salts, arginine salts, benzathine salts, calcium salts, choline salts, diethylamine salts, diolamine salts, glycine salts, lysine salts, magnesium salts, meglumine salts, olamine salts, potassium salts, sodium salts, tromethamine salts, and zinc salts. Hemisalts of acids and bases may also be formed, such as hemisulfate salts and hemicalcium salts. For a review of suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0071] The benzenesulfonamide thiazole compounds used in the context of the present invention can exist in both unsolvated and solvated forms. The term "solvate" refers to a molecular complex containing a benzenesulfonamide thiazole compound and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, such as ethanol. The term "hydrate" is used when the solvent is water. In contrast to the aforementioned solvates, complexes such as clathrates and drug-host inclusion complexes, in which the drug and host are present in stoichiometric or non-stoichiometric amounts, are also included. Complexes of drugs containing two or more organic and / or inorganic components, which may be in stoichiometric or non-stoichiometric amounts, are also included. The resulting complexes may be ionized, partially ionized, or non-ionized. For a review of such complexes, see Haleblian, J Pharm Sci, 64 (8), 1269-1288 (August 1975).

[0072] Thus, references to the benzenesulfonamide thiazole compounds of formula (I) include references to salts, solvates and complexes thereof, and solvates and complexes of salts thereof. References to the benzenesulfonamide thiazole compounds of formula (I) include all polymorphs and crystal habits thereof, prodrugs and isomers thereof (including optical isomers, geometric isomers and tautomers), and isotopically labeled compounds of formula (I).

[0073] [Therapeutic use] As noted above, the anti-cancer treatments and benzenesulfonamide thiazole compounds of the present invention are used in treating cancer in a patient.

[0074] Accordingly, the present disclosure provides a method of treating cancer comprising administering to a patient in need thereof a therapeutically effective amount of an anti-cancer treatment and a benzenesulfonamide thiazole as defined above.

[0075] According to the present invention, the anticancer treatment and the benzenesulfonamide thiazole compound are administered to a patient simultaneously, separately, or sequentially in any order. According to a specific embodiment, the anticancer treatment is administered after the benzenesulfonamide thiazole compound. In other words, the anticancer treatment is administered to a patient who has already been administered the benzenesulfonamide thiazole compound. According to another specific embodiment, the benzenesulfonamide thiazole compound is administered after the anticancer treatment. In other words, the benzenesulfonamide thiazole compound is administered to a patient who has already been administered an immune checkpoint inhibitor.

[0076] The terms "subject" and "patient" refer to a human or animal suffering from cancer. Typically, the patient is a mammal. The patient can be, for example, a human, a feline, such as a cat, a canine, such as a dog, or an equine, such as a horse. Preferably, the patient is a human.

[0077] The patients according to the present invention overexpress GRP78.

[0078] "78 kDa glucose-regulated protein" or "GRP78," also known as "binding immunoglobulin protein" (BiP) or "heat shock 70 kDa protein 5" (HSPA5), is a protein encoded by the HSPA5 gene in humans. GRP78 is an endoplasmic reticulum chaperone that plays an important role in protein folding and quality control in the endoplasmic reticulum lumen. The sequence of GRP78 can be found in the Uniprot database library under reference number P11021.

[0079] "Overexpression" means that the level of GRP78 measured in a biological sample obtained from a patient is significantly higher than the level measured in a control sample. Typically, the control sample can be a sample obtained from a control population or control tissue. A control population typically consists of healthy subjects, i.e., subjects not suffering from cancer or other diseases. A control tissue typically consists of healthy tissue, i.e., tissue not affected by disease. The control tissue is usually obtained from the patient himself. Several techniques are known to those skilled in the art that can determine whether a gene / protein is overexpressed compared to a control sample. Those skilled in the art are familiar with such techniques that are routinely used. Several papers have been published regarding the evaluation of GRP78 levels (see, for example, Huang et al. (2018). International Journal of Clinical and Experimental Pathology, 11(11), 5223). Typically, the level of GRP78 is considered "overexpressed" if the level is 1.5-fold, preferably 1.7-fold, and more preferably 2-fold higher than the level measured in a control population.

[0080] Typically, the GRP78 level measured is either a circulating GRP78 level or an intratumoral GRP78 level.

[0081] "Circulating GRP78" refers to the GRP78 protein present in a patient's circulating blood, typically in the cell-free portion of the patient's blood (plasma / serum). The level of circulating GRP78 protein is typically measured by assessing the amount of GRP78 in a blood sample, typically a plasma / serum sample, obtained from the patient. The control used to determine whether the level of circulating GRP78 is overexpressed is typically the GRP78 level measured in a blood sample from a control population.

[0082] "Intratumor GRP78" refers to the GRP78 protein expressed in a patient's tumor. The level of GRP78 protein is typically measured by assessing the amount of GRP78 expressed in a tumor sample obtained from a patient, typically a tumor biopsy. The control used to determine whether the level of intratumor GRP78 is overexpressed is typically the GRP78 level measured in a control tissue, i.e., a healthy tissue of the patient.

[0083] Those of skill in the art are familiar with the many techniques routinely used to determine the expression levels of proteins such as GRP78.

[0084] Such methods typically involve contacting the biological sample to be analyzed with an agent capable of specifically binding to the target protein. This agent is usually a polyclonal or monoclonal antibody. The presence of the protein is then typically detected by standard immunodetection methods after electrophoretic protein separation (a technique also known as "Western blotting") or by direct, indirect, competitive, or immunocapture immunoassays (a technique also known as "ELISA"). The formation of a complex between the protein of interest and an antibody targeting that protein is usually detected and quantified by measuring an enzymatic reaction that produces a colored, chemiluminescent, or fluorescent product, resulting in a specific staining pattern in terms of percent staining. Typically, "strong staining" is defined as positive staining of 50% or more of the tumor cells, "moderate staining" is defined as positive staining of 10% to less than 50% of the tumor cells, and "weak staining" is defined as positive staining of less than 10% of the tumor cells (Samanta et al., 2022).

[0085] Currently, several kits are available for measuring plasma / serum GRP78 levels, for example, the ELISA kit commercially available from Enzo Life Sciences under the reference number ADI-900-214 can be used.

[0086] The intratumor GRP78 level can also be determined by determining the density of GRP78-expressing cells. Typically, a method for measuring the density of GRP78-expressing cells includes contacting a tumor tissue sample with at least one selective binding agent capable of selectively interacting with GRP78. The selective binding agent can be a polyclonal or monoclonal antibody, an antibody fragment, a synthetic antibody, or other protein-specific agents such as nucleic acid or peptide aptamers. Several antibodies specific for GRP78 are known to those skilled in the art. Many of these antibodies are commercially available. Immunohistochemistry is particularly suitable for assessing the density of GRP78 cells. Typically, a tissue tumor sample is first incubated with a labeled antibody against GRP78. After washing, the labeled antibody bound to GRP78 is revealed by an appropriate technique depending on the type of label (e.g., radioactive, fluorescent, or enzymatic) carried by the labeled antibody.

[0087] The level of GRP78 can also be measured by measuring the amount of mRNA produced by the HSPA5 gene. Methods for measuring the amount of mRNA are well known in the art. For example, nucleic acids contained in a sample are first extracted according to standard methods, for example, using lytic enzymes or chemical solutions, or extracted with nucleic acid-binding resins according to the manufacturer's instructions. The extracted mRNA is then detected by hybridization (e.g., Northern blot analysis) and / or amplification (e.g., RT-PCR). Quantitative or semi-quantitative RT-PCR is a preferred method.

[0088] Thus, according to certain embodiments, the present disclosure provides a method of treating cancer in a patient, comprising measuring the level of GRP78 in a tumor or a blood / plasma / serum sample obtained from said patient, and then, if said patient is identified as overexpressing GRP78, administering a therapeutically effective amount of an anti-cancer treatment and a benzenesulfonamide thiazole as defined above.

[0089] For the avoidance of doubt, references herein to "treatment" include references to curative, palliative and prophylactic treatment. "Treatment" is intended to ameliorate, alleviate, inhibit the progression of or prevent the disorder or condition to which the term applies, or to ameliorate, alleviate, inhibit the progression of or prevent one or more symptoms of the disorder or condition to which the term applies.

[0090] As used herein, the term "cancer" refers to a physiological condition in a subject characterized by unregulated or dysregulated cell growth or cell death. The term "cancer" includes solid tumors and hematological tumors.

[0091] Typically, the combination for use according to the present invention is applied to various organs of origin of cancer (breast, colon, stomach, rectum, pancreas, lung, skin, head and neck, bladder, ovary, prostate, etc.) and to various cancer cell types (adenocarcinoma, squamous cell carcinoma, large cell carcinoma, melanoma, etc.).

[0092] In certain embodiments, the patient has skin cancer (e.g., melanoma, non-melanoma skin cancer), colorectal cancer, adrenocortical carcinoma, anal cancer, bile duct cancer (e.g., periphilarcinoma), or the like. cancer), distal bile duct cancer, intrahepatic bile duct cancer), bladder cancer, bone cancer (e.g., osteoblastoma, osteosarcoma, chondrosarcoma, fibrosarcoma, malignant fibrous histiocytoma), sarcomas such as liposarcoma and soft tissue sarcoma, brain and central nervous system cancer (e.g., meningioma, astrocytoma, oligodendroglioma, ependymoma, glioma, medulloblastoma, ganglioglioma, schwannoma, germinoma, craniopharyngioma), breast cancer (e.g., ductal carcinoma in situ, invasive ductal carcinoma, invasive lobular carcinoma, lobular carcinoma in situ), cervical cancer, endometrial cancer (e.g., endometrial adenocarcinoma, adenocarcinoma, papillary serous adenocarcinoma), esophageal cancer, gallbladder cancer (mucinous adenocarcinoma, small cell carcinoma), gastrointestinal carcinoid tumors (e.g., choriocarcinoma, destructive villous adenoma), kidney cancer (e.g., renal cell carcinoma) The patient is suffering from a solid cancer selected from the group consisting of: laryngeal and hypopharyngeal cancer, liver cancer (e.g., hepatic adenoma, hepatocellular carcinoma), lung cancer (e.g., small cell lung cancer, non-small cell lung cancer), mesothelioma, nasal cavity and paranasal sinus cancer (e.g., nasal neuroblastoma, midline granuloma), nasopharyngeal cancer, neuroblastoma, oral cavity and oropharyngeal cancer, ovarian cancer, pancreatic cancer, penile cancer, pituitary cancer, prostate cancer, retinoblastoma, rhabdomyosarcoma (e.g., embryonal rhabdomyosarcoma, alveolar rhabdomyosarcoma, pleomorphic rhabdomyosarcoma), salivary gland cancer, gastric cancer, testicular cancer (e.g., seminoma, non-seminomatous germ cell carcinoma), thymus cancer, thyroid cancer (e.g., follicular adenocarcinoma, undifferentiated carcinoma, poorly differentiated carcinoma, medullary thyroid carcinoma), vaginal cancer, vulvar cancer, and uterine cancer (e.g., uterine leiomyosarcoma).

[0093] In certain embodiments, the patient is suffering from a hematological cancer, such as leukemia, lymphoma (such as Hodgkin's lymphoma or non-Hodgkin's lymphoma), and myeloma.

[0094] The benzenesulfonamide thiazole compounds of the present invention have been shown to be highly effective against both sensitive and resistant cancer cell lines derived from melanoma, pancreatic cancer, and chronic myeloid leukemia (see Millet et al., Journal of medicinal chemistry 59.18 (2016): 8276-8292). Thus, according to another specific embodiment, the cancer treated according to the present invention is selected from the group consisting of skin cancer, pancreatic cancer, and leukemia.

[0095] According to a preferred embodiment, the cancer treated according to the present invention is colorectal cancer, gastric cancer, pancreatic cancer, breast cancer, lung cancer, or skin cancer (preferably melanoma).

[0096] According to certain embodiments, the cancer of the present invention is a non-immunogenic tumor. As used herein, the term "non-immunogenic tumor" refers to a tumor that does not induce a T cell response. Those skilled in the art are familiar with this concept and know how to determine whether a tumor is immunogenic (see, for example, Wang et al. Elife 8 (2019): e49020). Such tumors are generally associated with: - a low number of tumor-infiltrating lymphocytes and, accordingly, a low density of tumor-infiltrating lymphocytes, located either at the periphery or in the center of the tumor, as measured, for example, as described in the international application published under reference WO 2007 / 045996 or according to Immunoscore®; - CD8, also known as "Tex cells" + Exhausted populations of T cells (Wherry, E. John, and Makoto Kurachi, Nature Reviews Immunology 15.8 (2015): 486-499), which can be identified as shown in Bengsch et al. Immunity 48.5 (2018): 1029-1045; - Restricted tumor antigen presentation (as shown in Wang (2019)); - a large number of M2 macrophages and myeloid-derived suppressor cells; and / or - Type 2 inflammatory tumor microenvironment (see, for example, Gajewski et al. Tumor immune microenvironment in cancer progression and cancer therapy (2017): 19-31 or Trujillo et al. Cancer immunology research 6.9 (2018): 990-1000).

[0097] According to another embodiment, the cancer according to the present invention is "resistant" to immunotherapy, meaning that the patient does not respond or responds poorly to immunotherapy, particularly immune checkpoint inhibitor monotherapy.

[0098] As used herein, the term "responder" refers to a patient who shows a response, i.e., a patient whose cancer is eradicated, regressed, or stabilized after treatment. Non-responder, or refractory, patients include those whose cancer does not regress or stabilize after immunotherapy, particularly immune checkpoint therapy.

[0099] The compounds used in the context of the present invention can be administered by any suitable route. Those skilled in the art know which administration route to use and the corresponding dosage. The compounds useful in the context of the present invention are typically administered parenterally (for example, intravenously, intramuscularly, or subcutaneously) or orally.

[0100] The present invention is further illustrated by the following figures and examples, which, however, should not be construed in any way as limiting the scope of the present invention.

[0101] BRIEF DESCRIPTION OF THE DRAWINGS Figure 1: CT26 cells (5.10 4 ) was subcutaneously injected into Balb / C mice. 3Immediately after reaching 800 mm , mice were randomly assigned to different experimental groups and treated daily (i.p.) with vehicle or HA15 (35 mg / kg), and twice weekly with anti-PD1 (6.25 mg / kg) or PBS for 2 weeks. A: Individual tumor growth curves. B: Survival curves. Mice were maintained until tumors reached 800 mm . 3 The animals were euthanized when they reached a normal age. A log-rank (Mantel-Cox) test was performed to statistically compare the survival rates in different experimental groups. Ns = no significant difference, *: p ≤ 0.05, **: p ≤ 0.01, ***: p ≤ 0.001.

[0102] Figure 2: HA15 induces CHOP and IFN-g expression in mouse tumors in vivo. Tumors were harvested from mice after HA15 treatment and disrupted in lysis buffer to obtain protein lysates. (A) Tumor lysates were analyzed by Western blotting using CHOP, IFN-g, and HSP90 antibodies. Densitometry analysis was performed on the radiograms shown here using the ImageJ (Fiji) program. The signal intensity of the target protein was weighted by the signal intensity of the HSP90 control. (B) Intratumoral IFN-g in the lysates was measured using a mouse IFN-g ELISA kit. Protein expression in the two different groups was statistically compared using the Mann-Whitney test.

[0103] Figure 3: Graph showing the change in intratumoral GRP78 levels measured in mice treated with a combination therapy according to the present invention compared to monotherapy containing either HA15 (BPR001) or anti-PDL1 alone.

[0104] [Example] Example 1: Combination of HA15 and anti-PD1 antibody in CT26 tumor model Materials and Methods

[0105] [CT26 allograft experiment] Five-week-old female BALB / cOlaHsd mice were obtained from Envigo Laboratory. One week later, these mice were inoculated with CT26 cells (5 × 10 5The tumors were subcutaneously inoculated with 1000 cells / mouse. 3 Immediately after reaching 100 mg / day, each mouse was assigned to a different experimental group (7 mice / group) according to a randomization table generated by the "Graphpad Quickcalcs" tool. Animals were then intraperitoneally inoculated with DMA / Tween80 / Labrafil (9 / 1 / 90) + PBS (control group), HA15 in Labrafil (0.7 mg / mouse / day) + PBS (HA15 group), anti-PD1 antibody (in vivo MAb anti-mouse PD1 (CD279) antibody / catalog no. BE0146 / clone: ​​RPM1-14) in PBS (4 injections at 0.125 mg / mouse on treatment days 1, 4, 8, and 11) + Labrafil (anti-PD1 group), or a combination of HA15 and anti-PD1 treatment (HA15 + anti-PD1 group). Tumor volume was calculated as volume = (length × width). 2 ) / 2. 3 At that time, mice were anesthetized with ketamine (100 mg / kg) / xylasine (10 mg / kg) injection, and retroorbital blood samples were collected. After sacrificing the mice by cervical dislocation, lymph nodes and tumors were harvested for Western blot and ELISA experiments.

[0106] The survival curve is 3 The percentage of mice reaching 0.05 (= death event) is shown for each time point. A log-rank (Mantel-Cox) test was performed to statistically compare survival rates in different experimental groups. Ns = no significant difference; *: p ≤ 0.05; **: p ≤ 0.01; ***: p ≤ 0.001.

[0107] Analysis of intratumor proteins by Western blot and ELISA Tumor fragments were homogenized in CK Mix Tubes (#P000918-LYSK0, Bertin Technologies) using a Precellys 24 Tissue Homogenizer in the presence of protein lysis buffer containing 50 mmol / L Tris-HCl (pH 7.5), 15 mmol / L NaCl, 1% Triton X-100, and 1x protease and phosphatase inhibitors. The tumor lysate was then centrifuged to remove cellular debris.

[0108] For Western blots, tumor lysates were prepared in Laemmli buffer. Briefly, tumor lysates (30 μg) were separated by SDS-PAGE, transferred to polyvinylidene difluoride membranes (Millipore), and exposed to the appropriate antibodies. Antibodies against IFN-gamma were purchased from Abcam (ab133566). Proteins were visualized using the Amersham ECL system. The Western blot analysis shown is representative of at least three independent experiments.

[0109] Intratumoral IFN-gamma was administered in the same lysate using a Cusabio mouse interferon-g ELISA kit (#CSB-E04578m). Briefly, 75 μg of tumor lysate (or standard sample) was added to a plate precoated with an IFN-gamma-specific antibody. After removing unbound material, a biotin-conjugated antibody specific for IFN-gamma was added to the wells. Next, avidin-conjugated horseradish peroxidase (HRP) was incubated, followed by the addition of a substrate solution. Color development was proportional to the amount of IFN-gamma bound in the first step. Statistical analysis was performed using the Mann-Whitney test. Ns = not significant; *: p ≤ 0.05; **: p ≤ 0.01; ***: p ≤ 0.001.

[0110] [Serum protein analysis by ELISA] Mouse blood (500 μL) was directly transferred to tubes containing a clot activator (Microvette 500ZGel #20-1344, Sarstedt) and centrifuged at 10,000 g for 5 minutes to collect serum. Serum IFN-gamma was measured in 100 μL of these samples using a Cusabio mouse interferon-g ELISA kit (#CSB-E04578m) as described above. Statistical analysis was performed using the Mann-Whitney test. Ns = not significant; *: p ≤ 0.05; **: p ≤ 0.01; ***: p ≤ 0.001.

[0111] 〔result〕 As shown in Figure 1, combination therapy with HA15 and anti-PD-1 antibody significantly improved survival and reduced tumor growth in a mouse synthetic immunodeficiency model of colorectal cancer compared with either HA15 monotherapy (14% complete response rate) or anti-PD-1 monotherapy (33% complete response rate). The combination of HA15 and anti-PD-1 immunotherapy (anti-PD-1) resulted in a 100% survival rate after 40 days.

[0112] We further demonstrated that HA15 induced the expression of CHOP and IFNγ in CT26 tumors (see Figure 2), demonstrating its ER (endoplasmic reticulum) stress-regulating mediated effect, implying that HA15 can reactivate CD8+ T cell lymphocytes through its mechanism of action, leading to the release of IFNγ.

[0113] We further demonstrated that immune stimulation was localized to the tumor and did not affect the liver, where no changes in CHOP and IFNγ expression were observed after HA15 treatment (data not shown).

[0114] These results demonstrate that HA15 can enhance anti-PD1 responses and can be used to convert non-immunogenic tumors into immunogenic tumors that are sensitive to treatment with, for example, immune checkpoint inhibitors.

[0115] Example 2: Combination of HA15 and anti-PDL1 antibody in CT26 tumor model [A-Protocol] Mice: Sixty female BALB / C mice, 5 weeks old and weighing 15-19 g, were purchased from Envigo. These mice were acclimated for one week in the C3M animal facility. Animals were housed in IVC cages (5 per cage) and individually identified by ear tags. All animals had free access to standard certified commercial chow and sterilized water throughout the study. The animal room was maintained under standard conditions: 18-24°C, 55-70% humidity, and a 12-hour light-dark cycle. Two mice died during blood collection one week before the start of dosing.

[0116] All protocols used in this study were approved by the C3M Health and Ethics Committee.

[0117] 58 mice were randomly assigned to the following treatment groups:

[0118] [Table 1]

[0119] Cells: CT26 cell line was thawed 2 weeks before the arrival of mice. CT26 cell line was cultured in RPMI medium supplemented with 10% FBS, 1% penicillin / streptomycin, and 2% sodium pyruvate. Cells were cultured at 0.8 × 10 cells / ml in 5 × T175 flasks 48 hours before subcutaneous injection. 6 Cells were grown at a concentration of 0.5 × 10 cells per flask. At this concentration, cells were 70–80% confluent on the day of injection. Briefly, cells were washed with PBS, detached from the flask using 3 ml of trypsin, collected in RPMI medium, and centrifuged at 300 g for 5 min. They were resuspended in PBS, counted, and collected at 0.5 × 10 cells per flask. 6 Cells / mouse (32 million cells total for 80 mice) were harvested, recentrifuged, and resuspended in 100 μl / mouse of PBS, ready for subcutaneous injection (8 ml total for 80 mice).

[0120] 〔formulation〕 HA15: 15% Kolliphor H15, 10% PEG400, 5% ethanol, 70% ultrapure water.

[0121] 1- Compounds were formulated after mixing Kolliphor HS15, PEG400 and ethanol in appropriate ratios (3 / 2 / 1, v / v / v) in a sterile biosafety cabinet (Kolliphor HS15 was melted at 30°C). 2- An appropriate amount of HA15 compound was weighed on a microbalance and placed in a Wheaton vial. This compound was dissolved in the above solution with a magnetic bar, making 30% of the final vehicle volume. 3- After complete solubilization, ultrapure water (7 parts of the final vehicle volume) was added to the Wheaton vial and mixed well by vortexing.

[0122] Antibodies (anti-PDL1 and IgG2b) were diluted in PBS before IP injection.

[0123] [B-Result] After 13 days of treatment, the data showed that daily oral administration of HA15 reduced tumor volume. This reduction in CT26 tumor growth was statistically significant compared to the vehicle group. This was further confirmed by measuring tumor weights after sacrificing the mice on day 13.

[0124] Biweekly administration of anti-PDL1 and daily administration of HA15 significantly reduced CT26 tumors compared to the vehicle + IgG2b control group and the single-agent treatment (HA15) group.

[0125] These results also indicate that HA15 can enhance anti-PDL1 responses, and therefore we can conclude that HA15 can generally enhance the effects of immune checkpoint inhibitors.

[0126] The intratumoral levels of GRP78 in treated mice are shown in Figure 3. As shown in this figure, HA15 + anti-PDL1 combination therapy can significantly reduce the intratumoral levels of GRP78 in patients compared with monotherapy containing either HA15 or anti-PDL1 alone.

[0127] Example 3: Combination of HA15 with different anti-cancer treatments 〔method〕 Cell lines and reagents: Various cell lines were purchased from ATCC. Tumor cell lines were maintained in a humidified atmosphere at 37°C and 5% CO2, and supplemented with DMEM, high glucose, and GlutaMAX. TM Cells were cultured in supplemented pyruvate culture medium supplemented with 10% fetal bovine serum (ThermoFisher). Cells were treated with the indicated anticancer drugs and HA15 at the indicated concentrations and for the indicated time periods. All drugs were dissolved in DMSO.

[0128] Proliferation analysis: Cell proliferation was measured using Abcam's WST-1 reagent (#ab65473). On day 0, cells were plated in 96-well tissue culture plates. On day 1, cells were serum-starved (100 μL / well). On day 2, cells were treated with the indicated concentrations of different drugs or DMSO in quadruplicate. 48 hours after treatment, WST-1 reagent (10 μL / well) was added. Plates were read at 450 nm on a Multiskan FC Counter (ThermoScientific) at TO and every hour thereafter until an OD of 1.0 was reached. Cell proliferation was expressed as a percentage of absorbance after background (TO) subtraction.

[0129] Cells were treated with different concentrations of HA15 and different concentrations of the indicated anticancer drugs 48 hours before WST-1 assay.

[0130] To evaluate the efficacy of HA15 in combination with other anticancer drugs, we compared observed and predicted responses to the combination treatments. We used the Bliss model to predict the efficacy of each drug combination.

[0131] The expected effect in combination (Eexp) was estimated from each individual drug effect.

[0132] The results are shown in the table below, where "SE" corresponds to significant efficacy of the combination of HA15 with the identified anti-cancer agent.

[0133] [Table 2]

[0134] [Table 3]

[0135] [Table 4]

[0136] These results indicate that HA15 can enhance the response to several anti-cancer treatments, including chemotherapy and targeted therapy, and therefore it can be concluded that HA15 can enhance the efficacy of anti-cancer treatments. [Brief explanation of the drawings]

[0137] [Figure 1A] CT26 cells (5.104) were injected subcutaneously into Balb / C mice. As soon as tumors reached 50 mm3, mice were randomly assigned to different experimental groups and treated daily (intraperitoneally) with vehicle or HA15 (35 mg / kg), and twice weekly with anti-PD1 (6.25 mg / kg) or PBS for 2 weeks. A: Individual tumor growth curves. Mice were euthanized when tumors reached 800 mm3. A log-rank (Mantel-Cox) test was performed to statistically compare survival rates in different experimental groups. Ns = not significant; *: p ≤ 0.05; **: p ≤ 0.01; ***: p ≤ 0.001. [Figure 1B]CT26 cells (5.104) were subcutaneously injected into Balb / C mice. As soon as tumors reached 50 mm3, mice were randomly assigned to different experimental groups and treated intraperitoneally with vehicle or HA15 (35 mg / kg) daily, and with anti-PD1 (6.25 mg / kg) or PBS twice a week for 2 weeks. B: Survival curve. Mice were euthanized when tumors reached 800 mm3. A log-rank (Mantel-Cox) test was performed to statistically compare survival rates in different experimental groups. Ns = not significant; *: p ≤ 0.05; **: p ≤ 0.01; ***: p ≤ 0.001. [Figure 2] HA15 induces the expression of CHOP and IFNγ in mouse tumors in vivo. Tumors were harvested from mice after HA15 treatment and disrupted in lysis buffer to obtain protein lysates. (A) Tumor lysates were analyzed by Western blotting using CHOP, IFNγ, and HSP90 antibodies. Densitometry analysis was performed on the radiograms shown here using the ImageJ (Fiji) program. The signal intensity of the target protein was weighted by the signal intensity of the HSP90 control. (B) Intratumoral IFN-γ in the lysates was measured using a mouse IFN-γ ELISA kit. Protein expression in two different groups was statistically compared using the Mann-Whitney test. [Figure 3] 1 is a graph showing the change in intratumoral GRP78 levels measured in mice treated with a combination therapy according to the present invention compared to monotherapy comprising either HA15 (BPR001) or anti-PDL1 alone.

Claims

1. A combination of an anti-cancer treatment with a compound of formula (I): 【Chemistry 1】 During the ceremony, Q １ ~Q ５ are the same or different, and CR ６ represents R １ is a C ring containing one or two fused rings ６ ~C １０ aryl, where 2 to 5 carbon atoms are O, S, N, and NR ６ and R ６ , Halo, CN, NO ２ , C.F. ３ , OCF ３ , COOR ６ , O.C.O.R. ６ , S.O. ２ NR ６ R ７ , C.O.R. ６ R ７ , N.R. ６ R ７ , N.R. ６ COR ７ , (CH ２ ) ｐ－ NR ６ R ７ , (CH ２ ) ｐ－ OR ６ and (CH ２ ) Ｐ SR ６ is ultimately substituted with 5 to 11 substituents selected from R ２ is SO ２ R １ or R ６ and R ３ and R ４ are the same or different, and COR ８ and R ６ is selected from R ５ is R ６ , aryl, OR ６ , S.R. ６ , Halo, CN, NO ２ , C.F. ３ , OCF ３ , COOR ６ , S.O. ２ NR ６ R ７ , C.O.R. ６ R ７ , N.R. ６ R ７ and NHCOR ６ represents R ６ and R ７ are the same or different and represent H or alkyl, R ８ is selected from H, alkyl, cycloalkyl, aryl, alkylaryl, where aryl is selected from 1 to 4 R ５ may be substituted with a substituent, Or, R ８ is -(CH ２ ) ｑ -NR ６ R ７ represents p represents an integer of 0 to 6; q represents an integer of 0 to 6; wherein the thiazolyl group is linked to the six-membered group at the meta or para position relative to the sulfonamide group, and the thiazolyl group is linked to the six-membered group at the alpha or beta position relative to the S atom. A combination for use in treating cancer in a patient identified as overexpressing GRP78.

2. the anti-cancer treatment is selected from chemotherapeutic agents, targeted therapies, and immunotherapeutic agents such as immune checkpoint inhibitors; A combination for use according to claim 1.

3. the anti-cancer treatment is an immune checkpoint inhibitor that is an anti-PD-1 antibody or an anti-PDL1 antibody; A combination for use according to claim 1 or 2.

4. The compound of formula (I) is selected from the group consisting of: N-(4-(3-(5-(dimethylamino)naphthalene-l-sulfonamido)phenyl)thiazol-2-yl)acetamide 5-(dimethylamino)-N-(3-(2-(methylamino)thiazol-4-yl)phenyl)naphthalene-l-sulfonamide N-(4-(3-(5-(dimethylamino)naphthalene-1-sulfonamido)phenyl)thiazol-2-yl)-4-methylbenzamide N-(3-(2-aminothiazol-4-yl)phenyl)-5-(dimethylamino)naphthalene-1-sulfonamide N-(4-(3-(5-(dimethylamino)naphthalene-1-sulfonamido)phenyl)thiazol-2-yl)benzamide N-(4-(3-(5-(dimethylamino)naphthalene-1-sulfonamido)phenyl)thiazol-2-yl)pivalamide 2-Fluoro-N-(3-(2-(methylamino)thiazol-4-yl)phenyl)benzenesulfonamide N-(4-(4-(naphthalene-2-sulfonamido)phenyl)thiazol-2-yl)acetamide N-(4-(4-(5-(dimethylamino)naphthalene-1-sulfonamido)phenyl)thiazol-2-yl)acetamide N-(4-(4-(2-fluorophenylsulfonamido)phenyl)thiazol-2-yl)acetamide N-(4-(4-(2,4-difluorophenylsulfonamido)phenyl)thiazol-2-yl)acetamide N-(4-(4-(3-(trifluoromethyl)phenylsulfonamido)phenyl)thiazol-2-yl)acetamide N-(4-(3-(3-(trifluoromethyl)phenylsulfonamido)phenyl)thiazol-2-yl)acetamide N-(4-(4-(4-(trifluoromethyl)phenylsulfonamido)phenyl)thiazol-2-yl)acetamide N-(4-(3-(4-methylphenylsulfonamido)phenyl)thiazol-2-yl)acetamide N-(4-(3-(2-nitrophenylsulfonamido)phenyl)thiazol-2-yl)acetamide N-(4-(3-(3-nitrophenylsulfonamido)phenyl)thiazol-2-yl)acetamide N-(4-(3-(phenylsulfonamido)phenyl)thiazol-2-yl)acetamide N-(4-(3-(methylsulfonamido)phenyl)thiazol-2-yl)acetamide N-(4-(4-(4-methylphenylsulfonamido)phenyl)thiazol-2-yl)acetamide, and N-(4-(3-(5-(dimethylamino)naphthalene-l-sulfonamido)phenyl)thiazol-2-yl)-6-amino-hexanamide; A combination for use according to any one of claims 1 to 3.

5. The compound is of formula (III): 【Chemistry 2】 A combination for use according to any one of claims 1 to 4.

6. The cancer is selected from the group consisting of breast cancer, bladder cancer, cervical cancer, colorectal cancer, pancreatic cancer, head and neck cancer, Hodgkin's lymphoma, liver cancer, lung cancer, kidney cancer, skin cancer and gastric cancer; A combination for use according to any one of claims 1 to 5.

7. the cancer is colorectal cancer; A combination for use according to any one of claims 1 to 6.

8. The cancer is a skin cancer, preferably a melanoma. A combination for use according to any one of claims 1 to 6.

9. the cancer is a non-immunogenic tumor; A combination for use according to any one of claims 1 to 8.

10. the cancer is resistant to immunotherapy; A combination for use according to any one of claims 1 to 9.

11. the cancer is resistant to an immune checkpoint inhibitor. A combination for use according to claim 10.

12. - anticancer drugs; and - comprising a compound of formula (I) 【Transformation 3】 During the ceremony, Q1 to Q5 are the same or different and represent CR6; R1 represents a C6-C10 aryl containing one or two fused rings, in which 2 to 5 carbon atoms may be replaced by heteroatoms selected from O, S, N and NR6, and is ultimately substituted with 5 to 11 substituents selected from R6, halo, CN, NO2, CF3, OCF3, COOR6, OCOR6, SO2NR6R7, CONR6R7, NR6R7, NR6COR7, (CH2)p-NR6R7, (CH2)p-OR6 and (CH2)PSR6; R2 is SO2R1 or R6, R3 and R4 are the same or different and are selected from COR8 and R6; R5 represents R6, aryl, OR6, SR6, halo, CN, NO2, CF3, OCF3, COOR6, SO2NR6R7, CONR6R7, NR6R7 and NHCOR6; R6 and R7 are the same or different and represent H or alkyl; R8 is selected from H, alkyl, cycloalkyl, aryl, alkylaryl, where the aryl is optionally substituted with 1 to 4 R5 substituents which are the same or different; or R8 represents —(CH2)q-NR6R7; p represents an integer of 0 to 6; q represents an integer of 0 to 6; wherein the thiazolyl group is linked to the six-membered group at the meta or para position relative to the sulfonamide group, and the thiazolyl group is linked to the six-membered group at the alpha or beta position relative to the S atom. Parts kit.

13. For use in treating cancer in patients identified as overexpressing GRP78, 13. The kit of parts of claim 12.

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